Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
  • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• TBIs Alzheimer's disease.
• One long term consequence of TBIs is the reduced dendritic spine density in key areas of the brain.
• This invention provides for compounds that promote spinogenesis and/or are capable of reducing the neural toxicity of beta-amyloid peptides.
• the invention provides a compound according to Formula I and/or Formula IA:
• n and p are independently selected from 0, 1 or 2;
• each R 1 is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, thiol, and nitro;
• W is selected from the group consisting of -0-, -S-, -SO-, -S(0)2-, and -NR -, wherein R 12 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl;
• X is selected from the group consisting of -0-, -S-, -SO-, -S(0)2-, and -NR 12 -,
• R 12 is as defined above, provided that when A is arylene, and Y is -S- or -NR 12 -, then X is not -S-;
• Y is selected from the group consisting of -0-, -S-, -SO-, S(0)2-, and -NR 12 -, wherein R 12 is as defined above;
• Z is selected from the group consisting of -N(CH 3 )2CH2CH 2 OC(0)CH3 and
• R 13 is selected from the group consisting of hydrogen and methyl
• T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L- monosaccharide, and -L-oligosaccharide, wherein L is selected from the group consisting of a bond, phosphate, and sulfate.
• the invention provides a compound according to Formula II, Formula III, Formula IV, Formula V, and/or Formula VI:
• R 1 , R 12 , A, Y, Z, n and p are as defined above;
• subscript m is selected from 0, 1 or 2.
• Y is selected from the group consisting of -0-, -S-, and -NR 12 -, wherein R 12 is as defined above.
• T is hydrogen
• the invention provides a compound as described herein, pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, selected from:
• the invention provides a compound according to Formula VII:
• n and p are independently selected from 0, 1 or 2;
• subscript q is an integer selected from 2 to 8.
• each R 1 and R 2 are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.
• subscript q is an integer selected from 3 to 6;
• R 1 is selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH 2 , -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH 3 ) 2 , -SCH3, and -SO2NH2;
• R 2 is selected from the group consisting of halo, -CH 3 , -CH2CH3, cyclopentyl, -CF 3 , -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH 2 ) 2 OCH3, -CONH2, -CON(CH 3 ) 2 , -CH 2 S0 2 N(CH3)2, -OCH3, -OCF3, -OCH(CH 3 ) 2
• subscripts n and p are independently selected from 0 or 1, provided that subscripts n and p are not both 1.
• the invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein, selected from:
• R 1 is selected from the group consisting of halo, -CH 3 , -OCH3, phenyl, and -CN; and R 2 is selected from the group consisting of halo, -CH 3 , -CF 3 , -OCH3, -OCF3, -CHCH2, -CH2CHCH2, phenyl, and -NO2.
• the invention provides a compound according to Formula Vila:
• subscript q is an integer selected from 4 or 6;
• R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, halo, -CH 3 , and -OCH3; and R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrog halo, -CH 3 , -CF 3 , -OCH3, -OCF3, phenyl, -NO2;
• the invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
• the invention provides the following compound, or pharmaceutically acceptable salt or solvate thereof: [0016] In one embodiment, the invention provides a pharmaceutical composition containing a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
• the invention provides a method for increasing dendritic spine density of neurons.
• the method includes contacting the neurons with a therapeutically effective amount of a compound, or pharmaceutically acceptable salt or solvate thereof, or a composition as described herein under conditions sufficient to increase dendritic spine density of neurons.
• the method for increasing dendritic spine density of neurons is conducted subsequent to a traumatic brain injury.
• the invention provides a method for decreasing the neurotoxicity of beta-amyloid peptides to neurons.
• the method includes contacting the beta- amyloid peptides with a therapeutically effective amount of a compound, or pharmaceutically acceptable salt or solvate thereof, or a composition as described herein under conditions sufficient to decrease the neurotoxicity of the beta-amyloid peptides.
• the invention provides a method for reducing the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury.
• the method of reducing the symptoms of traumatic brain injury in a patient includes administering a therapeutically effective amount of a compound, or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition as described herein, wherein the
• therapeutically effective amount of the compound, or pharmaceutically acceptable salt or solvate thereof is an amount sufficient to reduce the symptoms of traumatic brain injury.
• the method for reducing the symptoms of traumatic brain injury in a patient is conducted within about 0 to 72 hours of the traumatic brain injury.
• the reduction of the symptoms of trauma is measured by an improvement in the performance of one or more functional domains by at least 20% to 30% within about 7 days of treatment as compared to the performance of the one or more functional domains measured prior to treatment but after injury.
• FIG. 1 Chemical structures of Benzothiazole-I (i.e., ((4-(6-methylbenzo[d]thiazol- 2-yl)phenyl)amino)-(CH 2 CH 2 0)4H), Benzothiazole-II (i.e., ((4-(benzo[d]thiazol-2- yl)phenyl)thio)-(CH 2 CH 2 0)6H), Benzothiazole-IIIA (i.e., ((4-(benzo[d]thiazol-2- yl)phenoxy)-(CH 2 CH 2 0)eH), and Benzothiazole-IIIB (i.e., ((4-(benzo[d]thiazol-2- yl)phenoxy)-(CH 2 CH 2 0)4H), as indicated.
• Benzothiazole-I i.e., ((4-(6-methylbenzo[d]thiazol- 2-yl)phen
• FIG. 2 The effect of benzothiazole compounds (5 ⁇ ) on the number of puncta from primary mouse cortical neurons (DIV 16) after 24 hours of treatment starting at DIV 15.
• FIG. 3 The effect of benzothiazole compounds (1 ⁇ ) on the synaptic density from primary mouse cortical neurons (DIV 16) after 24 hours of treatment starting at DIV 15.
• FIG. 4 A front view of four potential ligand binding pockets in human Fascin 1 (ribbon structure) are shown as grey-scale surfaces labeled A, B, C, and D.
• FIG. 5 A bottom view of the four potential ligand binding pockets in human Fascin 1 (ribbon structure) are shown as grey-scale surfaces labeled A, B, C, and D.
• FIG. 6 A top view of the four potential ligand binding pockets in human Fascin 1 (ribbon structure) are shown as grey-scale surfaces labeled A, B, C, and D.
• FIG. 7. A back view of the four potential ligand binding pockets in human Fascin 1 (ribbon structure) are shown as grey-scale surfaces labeled A, B, C, and D. [0030] FIG. 8. The docked complexes of human Fascin 1 (ribbon structure) and
• the pocket surface incorporates aromatic lipophilic surfaces, non-aromatic other (mostly aliphatic) lipophilic surfaces, hydrogen bonding acceptor potentials, and hydrogen bond donor potentials.
• FIG. 9 A 2D interaction diagram of Benzothiazole-I and human Fascin 1 complex. Areas with black circles represent hydrophobic region. Shading with black squares represents hydrogen bond acceptor. Dashed lines represent hydrogen bonds. Solid grey parabolas represent accessible surface for large areas. Broken thick line around compound shape indicates accessible surface. Size of residue ellipse represents the strength of the contact. 2D distance between residue label and ligand represents proximity. DETAILED DESCRIPTION
• the present invention provides compounds and compositions for promoting spinogenesis.
• the compounds and compositions of the present invention are useful for increasing dendritic spine density of neurons, and are also useful for decreasing the neurotoxicity of beta-amyloid peptides to neurons.
• Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-butyl ((CH 3 ) 3 C-), n-pentyl
• Alkenyl refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C 2- 3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C 3 , C 3 -4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1 , 2, 3, 4, 5 or more.
• alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1 ,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1 ,3-hexadienyl, 1 ,4-hexadienyl, 1 ,5-hexadienyl, 2,4-hexadienyl, or
• Alkenyl groups can be substituted or unsubstituted.
• Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
• aminosulfonylamino amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
• Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
• aminocarbonylamino aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
• Alkylene refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms, preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH 2 CH(CH 3 )- or -CH(CH 3 )CH 2 -), butylene (-CH2CH2CH2CH2-), isobutylene
• alkenylene refer to an alkylene moiety containing respective 1 or 2 carbon carbon double bonds.
• Substituted alkylene refers to an alkylene group having from 1 to 3 hydrogen atoms replaced with substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo wherein said substituents are defined herein.
• Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. "Substituted alkoxy” refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
• Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-.
• Acyl includes the "acetyl" group CH3C(0)-.
• Acylamino refers to the groups -NR 47 C(0)alkyl, -NR 47 C(0)substituted alkyl, -NR 47 C(0)cycloalkyl, -NR 47 C(0)substituted cycloalkyl, -NR 47 C(0)cycloalkenyl, -NR 47 C(0)substituted cycloalkenyl, -NR 47 C(0)alkenyl, -NR 47 C(0)substituted alkenyl, -NR 47 C(0)aryl, -NR 47 C(0)substituted aryl, -NR 47 C(0)heteroaryl, -NR 47 C(0)substituted heteroaryl, -NR 47 C(0)heterocyclic, and -NR 47 C(0)substituted heterocyclic, wherein R 47 is hydrogen or alkyl.
• Acyloxy refers to the groups alkyl-C(0)O, substituted alkyl-C(0)O, alkenyl-C(0)0-, substituted alkenyl-C(0)0, aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, cycloalkenyl-C(0)0-, substituted cycloalkenyl-C(0)0-, heteroaryl-C(0)0-, substituted heteroaryl-C(0)0-,
• heterocyclic-C(0)0- substituted heterocyclic-C(0)0-.
• R 48 and R 49 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SC -alkyl, -SC -substituted alkyl, -SC -alkenyl, -S02-substituted alkenyl, -SC -cycloalkyl, -SCh-substituted
• Aminocarbonyl refers to the group -C(O)NR 50 R 51 , wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
• Aminocarbonylamino refers to the group -NR 47 C(O)NR 50 R 51 , wherein R 47 is hydrogen or alkyl; R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
• Aminocarbonyloxy refers to the group -O-C(O)NR 50 R 51 , wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
• Aminosulfonyl refers to the group -SC NR 50 R 51 , wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
• Aminosulfonyloxy refers to the group -O-SO2NR 50 R 51 wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
• Aminosulfonylamino refers to the group -NR 47 SO2NR 50 R 51 , wherein R 47 is hydrogen or alkyl; R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
• Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g. , phenyl) or multiple condensed rings (e.g., naphthyl or anthryl).
• the condensed rings may or may not be aromatic (e.g. , 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like), provided that the point of attachment is at an aromatic carbon atom.
• Preferred aryl groups include phenyl and naphthyl.
• Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted
• Arylene refers to a divalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings.
• Substituted arylene refers to an arylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for aryl groups.
• Aryloxy refers to the group -0-aryl, wherein aryl is as defined herein. Exemplary aryloxy groups include phenoxy and naphthoxy.
• Substituted aryloxy refers to the group -0-(substituted aryl).
• Carboxyl or “carboxy” refers to -COOH, or salts thereof.
• Carboxyl ester or “carboxy ester” refers to the group -C(0)(0)-alkyl,
• (Carboxyl ester)amino refers to the group -NR 47 C(0)(0)-alkyl
• (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-aryl,
• cycloalkyl -0-C(0)0-cycloalkenyl, -0-C(0)0-substituted cycloalkenyl,
• Cycloalkyl refers to a saturated or partially unsaturated, monocyclic, fused bi cyclic or bridged poly cyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11, and C3-12.
• Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
• Saturated bicyclic and poly cyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane.
• Cycloalkenyl refers to cycloalkyl groups which are partially unsaturated, having one or more double or triple bonds in the ring.
• cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1 ,4-isomers),
• cycloalkyl is a saturated monocyclic C3-8 cycloalkyl
• exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• cycloalkyl is a saturated monocyclic
• C3-6 cycloalkyl exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Cycloalkyl and cycloalkenyl groups can be substituted or unsubstituted.
• Substituted cycloalkyl and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
• aminosulfonylamino amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.
• Cycloalkyloxy refers to -O-cycloalkyl. “Substituted cycloalkyloxy” refers to -0-(substituted cycloalkyl). [0068] “Cycloalkenyloxy” refers to -O-cycloalkenyl. “Substituted cycloalkenyloxy” refers to -0-(substituted cycloalkenyl).
• Halo or "halogen” refers to fluoro, chloro, bromo and iodo.
• "Hydroxy” or “hydroxyl” refers to the group -OH.
• Heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited
• Heteroaryl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5.
• Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
• the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3, 5 -isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
• heteroaryl groups can also be fused to aromatic ring systems, which may or may not contain a heteroatom, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, benzofuran, indolizine or benzothiene.
• benzopyrroles such as indole and isoindole
• benzopyridines such as quinoline and isoquinoline
• benzopyrazine quinoxaline
• benzopyrimidine quinazoline
• benzopyridazines such as phthalazine and cinnoline
• benzothiophene benzofuran
• the heteroaryl groups can be fused to non-aromatic ring systems, which may or may not contain a heteroatom, provided that the point of attachment is through an atom of the aromatic heteroaryl group.
• the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
• Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thizolyl, and
• heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine.
• Heteroaryl groups can be substituted or unsubstituted.
• substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
• Heteroaryloxy refers to -O-heteroaryl.
• Substituted heteroaryloxy refers to the group -0-(substituted heteroaryl).
• Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, or partially saturated, ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(0)2-.
• Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
• the heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members.
• Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
• heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine,
• heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.
• fused ring systems one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring.
• the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties.
• Heterocycloalkyl groups can be unsubstituted or substituted.
• Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
• Heterocyclyloxy refers to the group -O-heterocyclyl.
• heterocyclyloxy refers to the group -0-(substituted heterocyclyl).
• heterocyclyls and heteroaryls include, but are not limited to, azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imid
• Spirocycloalkyl and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:
• Substituted sulfonyl refers to the group -SC -alkyl, -SC -substituted
• cylcoalkyl -SC -cycloalkenyl, -S02-substituted cylcoalkenyl, -SC -aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic.
• Substituted sulfonyl includes groups such as methyl-SCh-, phenyl-SCh-, and 4-methylphenyl-S02-.
• Substituted sulfonyloxy refers to the group -OSC -alkyl, -OS02-substituted alkyl, -OSCh-alkenyl, -OS02-substituted alkenyl, -OS02-cycloalkyl, -OS02-substituted cylcoalkyl, -OS02-cycloalkenyl, -OS02-substituted cylcoalkenyl, -OSC -aryl,
• saccharide refers to a sugar, such as a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide.
• Monosaccharides include, but are not limited to, glucose, ribose and fructose.
• Disaccharides include, but are not limited to, sucrose and lactose.
• Oligosaccharides refers to 2 to 10 sugars linked together preferably through an alpha linkage. Examples of oligosaccharides include maltose, lactose, sucrose, and the like.
• Polysaccharides include, but are not limited to, cellulose, hemicellulose and lignocellulose or starch.
• Saccharides or sugars useful in the present invention include any and all naturally occurring sugars, such as, but not limited to, glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N-acetylglucosamine, fructose, sialic acid, including aldol and pyranose forms thereof, as well as D and L isomers thereof.
• a substituted ring can be substituted with one or more fused and/or spiro cycles.
• fused cycles include a fused cycloalkyl, a fused heterocyclyl, a fused aryl, a fused heteroaryl ring, each of which rings can be unsubstituted or substituted.
• spiro cycles include a fused cycloalkyl and a fused heterocyclyl, each of which rings can be unsubstituted or substituted.
• R', R" and R' each independently refer to hydrogen, unsubstituted alkyl, such as unsubstituted Ci-6 alkyl.
• heterocycloalkyl or heteroaryl ring as defined above
• Tautomer refers to constitutional isomers of organic compounds that readily convert by the chemical reaction of tautomerization or tautomerism. The reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. Tautomerism is a special case of structural isomerism and because of the rapid interconversion; tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors including, but not limited to, temperature, solvent and pH.
• Exemplary common tautomeric pairs include, but are not limited to, ketone and enol, enamine and imine, ketene and ynol, nitroso and oxime, amide and imidic acid, lactam and lactim (an amide and imidic acid tautomerism in heterocyclic rings), enamine and enamine and anomers of reducing sugars.
• Stepoisomer refers to isomeric molecules that have the same molecular formula and sequence of bonded atoms (i.e. constitution), but differ in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but the bond connection or their order differs. By definition, molecules that are stereoisomers of each other represent the same structural isomer.
• Enantiomers are two stereoisomers that are related to each other by reflection, they are non- superimposable mirror images. Every stereogenic center in one has the opposite configuration in the other. Two compounds that are enantiomers of each other have the same physical properties, except for the direction in which thy rotate polarized light and how they interact with different optical isomers of other compounds. Diastereomers and stereoisomers not related through a reflection operation, they are not mirror images of each other. These include meso compounds, cis- and trans- (E- and Z-) isomers, and non-enantiomeric optical isomers. Diastereomers seldom have the same physical properties.
• stereoisomers may refer to enantiomers, diastereomers or both. Stereoisomers are often obtained in partially purified form. For the compounds of this invention that possess stereoisomers, such partially purified forms include those having 60%, 70%, 80%, 90% or 95% of one dominant stereoisomer.
• the compounds of the present invention can be in salt form, such as acid or base salts of the compounds of the present invention.
• “Pharmaceutically acceptable salt” refers to salts of active compounds that are prepared with acids or bases, depending upon the particular substituents found on the compounds described herein.
• compositions acting as counter-ions to negative charge groups include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or other well- known salts.
• pharmaceutically acceptable salts acting as counter-ions to positively charged groups include carboxylic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, citric acid, tartaric acid, oxalic acid, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
• the compounds of the present invention can exist in unsolvated forms, or anhydrous forms, as well as solvated forms, including hydrated forms.
• Hydrates as the name infers, refer to complexation of molecules of water with each molecule of this invention.
• Solvates refer to complexation with an organic solvent such as methanol, ethanol, and isopropanol, and the like.
• the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
• Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms (e.g., anhydrates, solvates and hydrates) are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
• Poritional isomers or “constitutional isomers” refers to different compounds which have the same numbers of, and types of, of atoms, and hence the same molecular weight, but the atoms are connected differently.
• beta-amyloid refers to peptides of 36 to 43 amino acids that are involved in the formation of fibrils, plaques, and/or amyloid deposits by being enzymatically cleaved from amyloid precursor protein.
• the term also encompasses peptides having substantial similarity to amyloid-like proteins, such as, for example, structural variants. In some cases, the peptides occur naturally or can be synthetically constructed.
• beta-amyloid also includes amyloidgenic proteins and proteins that produce amyloidlike morphology.
• substantially similarity means that two peptide sequences, when optimally aligned, share at least 50% sequence identity, or at least 60% sequence identity, or at least 70% sequence identity, or at least 80% sequence identity, or at least 90% sequence identity, or at least 95% sequence identity or more (e.g., 99% sequence identity).
• residue positions, which are not identical, differ by conservative amino acid substitutions.
• Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains.
• a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic- hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains include methionine and cysteine.
• Preferred conservative amino acids substitution groups are valine-leucine-isoleucine; phenylalanine-tyrosine; lysine-arginine; alanine-valine; and asparagine-glutamine.
• residue positions, which are not identical are also composed of peptide analogs, including unnatural amino acids or derivatives thereof.
• Analogs typically differ from naturally occurring peptides at one, two, or a few positions, often by virtue of conservative substitutions. Some analogs also include unnatural amino acids or modifications of N or C terminal amino acids one, two, or a few positions.
• unnatural amino acids are D-amino acids, alpha, alpha-disubstituted amino acids, N-alkyl amino acids, lactic acid, 4-hydroxyproline, y-carboxyglutamate, epsilon- ⁇ , ⁇ , ⁇ - trimethyllysine, epsilon-N-acetyllysine, O-phosphoserine, N-formylmethionine, 3- methylhistidine, 5-hydroxylysine, omega-N-methylarginine, and isoaspartic acid.
• stereochemically pure as used herein with reference to a compound, means the compound or a composition thereof comprises predominantly one stereoisomer of the compound and is substantially free of other stereoisomer(s) of that compound.
• a stereochemically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
• a stereochemically pure composition of a compound having two or more chiral centers will be substantially free of other diastereomers of the compound.
• a typical stereochemically pure compound comprises about 80% by weight or greater of one stereoisomer of the compound and about 20% by weight or less of other stereoisomer(s) of the compound.
• a stereochemically pure compound comprises 90% by weight or greater of one stereoisomer of the compound and about 10% by weight or less of the other stereoisomer(s) of the compound; about 95% by weight or greater of one stereoisomer of the compound and about 5% by weight or less of the other stereoisomer(s) of the compound; about 97% by weight or greater of one stereoisomer of the compound and about 3% by weight or less of the other stereoisomer(s) of the compound; about 98% by weight or greater of one stereoisomer of the compound and about 2% by weight or less of the other stereoisomer(s) of the compound, and about 99% by weight or greater of one stereoisomer of the compound and about 1 % by weight or less of the other stereoisomer(s) of the compound.
• administering refers to any form of administration including oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the patient or subject. Suitable routes of administration are well known to the skilled artisan.
• therapeutically sufficient amount refers to an amount or dose of a compound of the present invention, or compositions thereof, that produces therapeutic effects for which it is administered.
• the therapeutically effective amount or dose can be an amount sufficient to increase dendritic spine formation, and/or an amount that reduces the neurotoxicity of abnormal protein structures, protein aggregates, or protein misfolding, such as amyloid plaques and/or amyloid deposits.
• Such deposits correlate to the patient's risk of, or presence of, diseases or conditions associated with beta-amyloid proteins, such as neurological diseases or conditions. In some cases, such diseases or conditions are referred to as amyloid based diseases or conditions.
• diseases and conditions include, for example, neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, diseases and/or conditions characterized by a loss of cognitive memory capacity such as, for example, mild cognitive impairment, Lewy body dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type) and the Guam Parkinson-Dementia complex.
• neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease
• diseases and/or conditions characterized by a loss of cognitive memory capacity such as, for example, mild cognitive impairment, Lewy body dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type) and the Guam Parkinson-Dementia complex.
• diseases and/or conditions which are based on or associated with beta- amyloid are progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, HIV-related dementia, ALS (amyotrophic lateral sclerosis), inclusion-body myositis (IBM), Adult Onset Diabetes, senile cardiac amyloidosis, endocrine tumors, and other diseases, including amyloid-associated ocular diseases that target different tissues of the eye, such as the visual cortex, including cortical visual deficits; the anterior chamber and the optic nerve, including glaucoma; the lens, including cataract due to amyloid-like deposition; the vitreous, including ocular amyloidosis; the retina, including primary retinal degenerations and macular degeneration, in particular age-related macular degeneration; the optic nerve, including optic nerve drusen, optic neuropathy and optic neuritis; and the cornea, including lattice dystrophy as well as cognitive loss due to brain injury either alone or in the aggregate (e.
• the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.
• the compounds and/or compositions of the present invention can be used alone or in combination with one or more further therapeutic agents. When used in combination, the compounds and/or compositions of the present invention can be administered simultaneously (i.e. concurrently) with one or more further therapeutic agents or consecutively with one or more further therapeutic agents. Consecutive administration is intended to encompass various orders of administration of the therapeutic agent(s) and the
• spinogenesis refers to the growth of new dendritic spines on neurons.
• dendrite refers to the branched extension of a neuron cell. Dendrites are typically responsible for receiving electrochemical signals transmitted from the axon of an adjacent neuron.
• dendritic spines or “dendrite spines” refer to protoplasmic protuberances on a neuron cell (e.g., on a dendrite).
• dendritic spines may be described as having a membranous neck which may be terminated with a capitulum (e.g., head), which are classified according to their shape: headless, thin, stubby, mushroom, or branched. Dendritic spinal density therefore refers to the total number of dendritic spines per unit length of a neuron cell.
• dendritic spine formation and the like refers to processes which lead to an increased number of dendritic spines or increased development of dendritic spines.
• dendritic spine morphology and the like refers to the physical characterization of a dendritic spine (e.g., shape and structure).
• Patient or “subject in need thereof refers to a living organism suffering from or prone to a condition that can be treated by administration of a compound or a pharmaceutical composition thereof, as provided herein.
• Non-limiting examples include humans, other mammals and other non-mammalian animals.
• Treatment refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any obj ective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
• the treatment or amelioration of symptoms can be based on objective or subj ective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
• disorders or conditions refer to a state of being or health status of a patient or subject capable of being treated with the compounds of the present invention.
• disorders or conditions include, but are not limited to low dendritic spine density of neurons, neurotoxicity of beta-amyloid peptides to neurons, and traumatic brain injury.
• Trauma refers to an acquired brain injury or a head injury, when a trauma causes damage to the brain. Trauma includes, e.g., post-head trauma, impact trauma, and other traumas to the head such as, for example, traumas caused by accidents and/or sports injuries, concussive injuries, penetrating head wounds, brain tumors, stroke, heart attack, meningitis, viral encephalitis, and other conditions that deprive the brain of oxygen.
• the trauma is an external, physical force.
• the trauma is a "blast-induced traumatic brain injury," which refers to a TBI caused by the direct or indirect exposure to an explosion.
• Blunt force impact refers to a brain injury when the head suddenly and violently hits an object but the object does not break through the skull.
• Concussion refers to a mild form of traumatic brain injury resulting in temporary impairment of neurological function which quickly resolves by itself, and where there are generally no gross structural changes to the brain as the result of the condition. A concussion is generally considered to occur when there is a blow to the head or other forceful event, resulting in loss of consciousness for less than 30 minutes.
• “Assessment” and “test” refer to an evaluation used to determine the severity of a traumatic brain injury, the details of which are described herein.
• "An amount sufficient to reduce the symptoms of traumatic brain injury” refers to the quantity of a compound administered to a patient suffering from a traumatic brain injury necessary to observe a reduction of the symptoms of traumatic brain injury in a patient.
• "Symptoms" of a traumatic brain injury may include elevated levels of biomarkers in a patient's blood. Examples of biomarkers that become elevated in the blood of a patient suffering from a traumatic brain injury are GFAP and UCH-L1.
• a sufficient amount of a compound administered to a patient having traumatic brain injury symptoms will cause at least a 20% to 30% reduction in the symptoms compared to a statistically significant cohort of patients with a traumatic brain injury who are not administered a sufficient amount of compounds.
• the present invention provides a compound of Formula I and/or Formula IA:
• n and p are independently selected from 0, 1 or 2;
• each R 1 is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, thiol, and nitro;
• W is selected from the group consisting of -0-, -S-, -SO-, -S(0)2-, and -NR -, wherein R 12 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl;
• X is selected from the group consisting of -0-, -S-, -SO-, -S(0)2-, and -NR 12 -,
• R 12 is as defined above, provided that when A is arylene, and Y is -S- or -NR 12 -, then X is not -S-;
• Y is selected from the group consisting of -0-, -S-, -SO-, S(0)2-, and -NR 12 -, wherein R 12 is as defined above;
• Z is selected from the group consisting -N(CH 3 )2CH2CH 2 OC(0)CH3 and
• R 13 is selected from the group consisting of hydrogen and methyl
• T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L- monosaccharide, and -L-oligosaccharide, wherein L is selected from the group consisting of a bond, phosphate, and sulfate.
• the present invention provides a compound according to Formula II, Formula III, Formula IV, Formula V, and/or Formula VI:
• R 1 , R 12 , A, Y, Z, n and p are as defined above;
• subscript m is selected from 0, 1 or 2.
• A is a heteroaryl (heteroarylene) group selected from pyridinylene, 1,3-imidazolylene, furanylene, pyrrolyene, thiophenylene, indolylene, and the like.
• A is an aryl (arylene) group, such as phenylene or naphthalyene.
• the invention provides a compound of Formula I and/or Formula I A, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the compound is selected from:
• the present invention provides a compound of Formula VII:
• subscripts n and p are independently selected from 0 to 4; subscript q is an integer selected from 1 to 20; and each R 1 and R 2 are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino,
• each R 1 and R 2 of Formula (VII) are independently selected from the group consisting of -F; -CI; -Br; -I; substituted or unsubstituted alkyl (e.g.
• each R 1 and R 2 of Formula (VII) are independently selected from the group consisting of -F; -CI; -Br; -I; substituted or unsubstituted alkyl (e.g.
• acyl acylamino; aminocarbonyl (e.g., amide or substituted amide); aminosulfonyl (e.g., sulfonamide or substituted sulfonamide); amino, substituted amino; substituted or unsubstituted aryl (e
• each R 1 and R 2 of Formula (VII) are independently selected from the group consisting of -F; -CI; -Br; -I; methyl; ethyl; n-propyl, isopropyl; substituted lower alkyl; vinyl; propenyl; methoxy; ethoxy; n-propoxy; acyl;
• acylamino aminocarbonyl; aminosulfonyl; amino; substituted amino; phenyl; carboxyl; carboxyl ester; cyano; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; hydroxyl; sulfonyl; substituted sulfonyl; thiol; thioalkyl; and nitro.
• each R 1 and R 2 of Formula (VII) are independently selected from the group consisting of halo, -CFb -OH, -CH2SO2NH2, -SO2NH2, -CH2CH3, cyclopentyl, -CF 3 , -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3, -(CH 2 ) 2 OCH 3 , -CONH2, -CON(CH 3 ) 2 , -CH 2 S0 2 N(CH 3 ) 2 , -OCH3, -OCF3, -OCH(CH 3 ) 2 , -N(CH 3 ) 2 , -NHCOCH3, -NO2, -SCH 3 , -S0 2 CH 3 , and -S0 2 N(CH 3 ) 2 .
• each R 1 of Formula (VII) is independently selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH 2 , -COCH 3 ,
• each R 2 of Formula (VII) is independently selected from the group consisting of halo, -CH 3 , -CH 2 CH 3 , cyclopentyl, -CF 3 , -CN, -CHCH 2 , -CH 2 CHCH 2 , phenyl, -C0 2 H, -CH 2 C0 2 H, -CH 2 CONH 2 , -COOCH 3 , -COCH 3 , -(CH 2 ) 2 OCH 3 , -CONH 2 , -CON(CH 3 ) 2 , -CH 2 S0 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -OCH(CH 3 ) 2 , -N(CH 3 ) 2 ,
• subscripts n and p of Formula (VII) are independently selected from 0 to 4. In some embodiments, subscripts n and p are independently 0, 1, 2, 3, or 4. In some embodiments, subscripts n and p are independently 0, 1, 2, or 3. In some other embodiments, subscripts n and p are independently 0, 1, or 2. In some embodiments, subscripts n and p are independently 0 or 1. In some embodiments, subscripts n and p are independently 0 or 1, provided that subscripts n and p are not both 1. In some embodiments, subscript n is 1 and subscript p is 0. In other embodiments, subscript n is 0 and subscript p is 1. In some embodiments, subscripts n and p are both 0.
• subscript q of Formula (VII) is an integer from 1 to 20.
• subscript q is an integer from 1 to 15, 2 to 14, 3 to 13, 4 to 12, 5 to 11, 6 to 10, or 7 to 9.
• subscript q can be an integer from 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, or 2 to 4.
• subscript q can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
• subscript q can be an integer from 2 to 8.
• subscript q can be an integer from 3 to 6.
• subscript q can be an integer from 4 to 6.
• subscript q can be 4 or 6.
• the present invention provides a compound of Formula VII:
• subscripts n and p are independently selected from 0, 1 or 2; subscript q is an integer selected from 2 to 8; and each R 1 and R 2 are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino,
• subscript q of Formula (VII) can be an integer selected from 3 to 6; subscripts n and p are independently selected from 0, 1 or 2; R 1 is selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH2, -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH 3 ) 2 , -SCH3, and -SO2NH2; and R 2 is selected from the group consisting of halo, -CH3, -CH2CH3, cyclopentyl, -CF3, -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, -CH2CONH2, -COOCH3, -COCH3,
• subscript q of Formula (VII) can be an integer selected from 3 to 6; subscripts n and p are independently selected from 0 or 1, provided that subscripts n and p are not both 1; R 1 is selected from the group consisting of halo, -OH, -CN, phenyl, -CHCH2, -COCH3, -COOCH3, -CH2SO2NH2, -NHCOCH3, -N(CH3)2, -SCH3, and -SO2NH2; and R 2 is selected from the group consisting of halo, -CH3, -CH2CH3, cyclopentyl, -CF 3 , -CN, -CHCH2, -CH2CHCH2, phenyl, -CO2H, -CH2CO2H, - CH2CONH2, -COOCH3, -COCH3, -(CH 2 ) 2 OCH3, -CONH2, -CON(CH 3 ) 2
• the compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof can be selected from:
• each R 1 of Formula (VII) is independently selected from the group consisting of halo, -CH3, -OCH3, phenyl, and -CN; and each R 2 of Formula (VII) is independently selected from the group consisting of halo, -CH3, -CF3, -OCH3, -OCF3, -CHCH2, -CH2CHCH2, phenyl, and -NO2.
• the present invention provides a compound, or a pharmaceutically acceptable salt or solvate thereof, according to Formula Vila:
• subscript q is an integer selected from 4 or 6;
• R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, halo, -CH3, and -OCH3; and,
• R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, -CH3, -CF3, - OCH3, -OCF3, phenyl, -NO2; wherein at least six of said R groups are hydrogen.
• the compounds of the present invention can be prepared from readily available starting materials by a variety of methods known to one of skill in the art (see Comprehensive Organic Transformations by Richard C. Larock, 1989) or by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the compounds of the invention are both readily apparent and accessible to those of skill in the relevant art.
• the discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds of the present invention.
• reaction temperatures, times, molar ratios of reactants, solvents, pressures, and the like are useful in the present invention.
• protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
• Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
• stereoisomers i.e., as individual enantiomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
• the starting materials and reagents used in preparing the compounds of the invention are available from commercial suppliers, such as, for example, Sigma- Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), and Emka-Cheme, (St. Louis, Missouri, USA).
• the starting materials and reagents used in preparing the compounds of the invention are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Vol. 1-28 (Wiley, 2016); March's Advanced Organic Chemistry, 7 th Ed.
• the starting materials and the intermediates of the reaction can be isolated and purified if desired using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including measuring physical constants and obtaining spectral data.
• the resulting oxide (ii) may then contacted with compound (Hi) (e.g., a 2-haloethanol or an alpha-halo omega hydroxyl poly oxy ethylene compound of from 2 to 10 repeating oxy ethylene groups), to form compound (iv), wherein q is as defined herein and Q is a halo group or leaving group (e.g., chloro, bromo, and iodo, or triflate, tosylate, and mesylate).
• compound (Hi) e.g., a 2-haloethanol or an alpha-halo omega hydroxyl poly oxy ethylene compound of from 2 to 10 repeating oxy ethylene groups
• Q is a halo group or leaving group (e.g., chloro, bromo, and iodo, or triflate, tosylate, and mesylate).
• Compounds such as, for example, commercially available (2-chloroethoxy)ethanol (Sigma Aldrich), 2-[(2-
• the resulting product, (iv) can be recovered by conventional means and purified by crystallization, chromatography, precipitation, and the like.
• the oxyalkylene chain of compound (iv) can be modified via the addition of a sugar or an oligosaccharide using standard procedures for generation of aglycons.
• Scheme 1 [0139] Starting compound (i) may be obtained using known synthetic routes and commercially available starting reagents.
• compound (i-a) can be produced from commercially available 2-bromobenzo[cf
• Compound (i-b) which can be optionally protected at the hydroxyl group), is converted to the corresponding boronic acid coupling partner, and subjected to conventional Suzuki conditions with (i-c) to provide for the 6-(benzo[cf
• Suzuki reactions are replete in the literature.
• compounds of Formula (VII) and Formula (Vila) can be prepared by the following approaches, summarized in Scheme 3 and described below. As shown in Scheme 3, the direct condensation of o-aminothiophenol (i) with / hydroxybenzaldehyde (ii), followed by an oxidative cyclization of the Schiff base intermediate to form the corresponding 2-substituted benzothiazole (Hi), can be catalyzed by any suitable acidic reagent, wherein R 1 , R 2 , n and p are as defined herein for Formula (VII) and Formula (Vila).
• a suitable Lewis acid catalyst e.g., FeCh, ZrOCh, In(OTf , Yb(OTf) 3 , or Sc(OTf» under suitable conditions results in the corresponding 2-substituted benzothiazole (Hi).
• the resulting benzothiazole (Hi) may then contacted with compound (iv) (e.g., a 2-substituted polyethylene glycol compound), to form compound (v), wherein q is as defined herein and Q is a halo group or leaving group (e.g., chloro, bromo, and iodo, or triflate, tosylate, and mesylate).
• the present invention provides a pharmaceutical composition, including a compound of the present invention described herein, or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, and one or more pharmaceutically acceptable excipients.
• Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient is a compound of Formula I, Formula IA, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula Vila, as described herein.
• the pharmaceutical composition contains a compound of Formula (VII) or Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof.
• compositions of the invention contain a therapeutically effective amount of the active ingredient.
• a therapeutically effective amount of the active ingredient is an amount effective to achieve its intended purpose.
• a therapeutically effective amount of the active ingredient can be an amount effective to increase dendritic spine density of neurons.
• a therapeutically effective amount of the active ingredient can be an amount effective to decrease the neurotoxicity of beta-amyloid peptides to neurons.
• a therapeutically effective amount of the active ingredient can be an amount effective to reduce the symptoms of traumatic brain injury.
• compositions will contain an amount of active ingredient effective to achieve the desired result. Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.
• compositions can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms.
• Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
• the compounds of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
• the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally.
• the compounds of the present invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75: 107-111, 1995).
• the present invention also provides pharmaceutical compositions including a pharmaceutically acceptable excipient and either a compound of the present invention, or a pharmaceutically acceptable salt of a compound of the present invention.
• pharmaceutically acceptable excipients can be either solid or liquid.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid excipient can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").
• the excipient is a finely divided solid, which is in a mixture with a finely divided compound of the instant invention.
• a compound of the instant invention is mixed with the excipient having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain from 5% or 10% to 70% of a compound of the instant invention.
• compositions typically include a conventional pharmaceutical excipient and may additionally include other medicinal agents, carriers, adjuvants, diluents, tissue permeation enhancers, solubilizers, and the like.
• the composition will contain about 0.01% to about 90%, preferably about 0.1% to about 75%, more preferably about 0.1% to 50%, still more preferably about 0.1% to 10% by weight of a compound of the present invention or a combination thereof, with the remainder consisting of suitable pharmaceutical excipients.
• Appropriate excipients can be tailored to the particular composition and route of administration by methods well known in the art, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, supra.
• Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; calcium phosphate; calcium silicate; talc; pectin; dextran, dextrin, and cyclodextrin inclusion complexes; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, dextrose, sucrose, mannitol, or sorbitol; starches including, but not limited to, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic, tragacanth, and acacia; as well as proteins including, but not limited to, gelatin, collagen; microcrystalline cellulose, water, saline, syrup, ethylcellulose, and polyacrylic acids such as Carbopols, e.g., Carbopol 941, Carbopol 980, Car
• lubricating agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates (i.e., the parabens); pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; and flavoring agents; biodegradable polymer beads.
• disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, alginates, or a salt thereof, such as sodium alginate.
• a pharmaceutically acceptable excipient may include physiologically acceptable compounds that act, for example, to stabilize the compounds of the present invention or modulate their absorption, or other excipients as desired.
• Physiologically acceptable compounds include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
• carbohydrates such as glucose, sucrose or dextrans
• antioxidants such as ascorbic acid or glutathione
• chelating agents such ascorbic acid or glutathione
• excipients should be nontoxic to recipients at the dosages and concentrations employed.
• preparation of such compositions entails combining the therapeutic agent with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, maltose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
• buffers such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, maltose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
• antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, maltose, sucrose or dextrins
• chelating agents such as EDTA,
• Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of compound (i.e., dosage).
• compositions of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
• Push-fit capsules can contain compounds of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
• the compounds of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
• a compound of the instant invention is dispersed homogeneously therein, as by stirring.
• the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
• Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
• liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
• Aqueous solutions suitable for oral use can be prepared by dissolving a compound of the instant invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
• Aqueous suspensions suitable for oral use can be made by dispersing the finely divided compound in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,
• hydroxypropylmethylcellulose sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).
• a naturally occurring phosphatide e.g., lecithin
• the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
• preservatives such as ethyl or n-propyl p-hydroxybenzoate
• coloring agents such as ethyl or n-propyl p-hydroxybenzoate
• flavoring agents such as sucrose, aspartame or saccharin.
• sweetening agents such as sucrose, aspartame or saccharin.
• Formulations can be adjusted for osmolality.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions.
• These preparations may contain, in addition to the compound of the instant invention, colorants, flavors, stabilizers, buffers, artificial and natural sweet
• Oil suspensions can be formulated by suspending a compound of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these.
• the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
• These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
• an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997.
• the pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions.
• the oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
• Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono- oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
• the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
• compositions containing a compound of the instant invention i.e., active ingredient
• the active ingredient can be a compound of Formula (VII) or Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof.
• the active ingredient can be a compound, or a pharmaceutically acceptable salt or solvate thereof, according to formula:
• magnesium stearate 2 [0161] The ingredients of Table 3 are mixed to form a suspension for oral administration.
• Witepsol® H-15 is a mixture of saturated vegetable fatty acid triglycerides, which is commercially available (e.g., Riches-Nelson, Inc., New York). Table 5. Suppository formulation
• the dosage and frequency (single or multiple doses) of a therapeutically effective amount of the compounds described herein administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another condition or disease; its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems.
• Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the present invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.
• the therapeutically effective amount can be initially determined from cell culture assays.
• Target concentrations will be those
• therapeutically effective amounts for use in humans can also be determined from animal models.
• a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
• the dosage in humans can be adjusted by monitoring compounds' effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
• Dosages may be varied depending upon the requirements of the patient and the compound being employed.
• the dose administered to a patient in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
• the dose of the compound administered to a patient can be effective or sufficient to increase dendritic spine density of neurons in the patient.
• the dose of the compound administered to a patient can be effective or sufficient to decrease the neurotoxicity of beta-amyloid peptides to neurons in the patient.
• the dose of the compound administered to a patient can be effective or sufficient to reduce the symptoms of traumatic brain injury in the patient.
• the size of the dose can be determined by the existence, nature, and extent of any adverse side-effects.
• Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
• an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient.
• This planning can involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
• the present invention provides a method for increasing dendritic spine density of neurons, which involves contacting the neurons with a
• the present invention provides a method for increasing dendritic spine density of neurons, which involves contacting the neurons with a therapeutically effective amount of a compound of Formula VII and/or Formula Vila, or a pharmaceutical composition thereof.
• the method for increasing dendritic spine density of neurons is conducted subsequent to a traumatic brain injury which puts a patient at risk of cognitive loss (either in the short term or long term).
• Such brain injuries include traumatic brain injuries well known in the art, as well as other repeated brain injuries, the cumulative effect of which is similar to a traumatic brain injury in that it places a patient at risk of cognitive loss (e.g., repeated concussions, transient ischemic events, and the like).
• cognitive loss e.g., repeated concussions, transient ischemic events, and the like.
• dendritic spines act as sites of learning in memory in the brain.
• Song, et al "A tetra(ethylene glycol) derivative of benzothiazole aniline amerliorates dendritic spine density and cognitive function in a mouse model of Alzheimer's disease” Exp. Neuro., 252: 105-113 (2014) which is incorporated herein by reference in its entirety.
• binding of small molecules to beta-amyloid inhibits formation of oligomers such as beta-sheets that neurotoxic.
• loss of spine density occurs in neurodegenerative diseases including Alzheimer's disease,
• the methods of this invention provide a means to offset these loses and, therefore, mitigate the symptoms of such diseases.
• the present invention provides a method for decreasing the neurotoxicity of beta-amyloid peptides to neurons, which involves contacting the beta- amyloid peptides with a therapeutically effective amount of a compound of the instant invention (i.e., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula Vila) under conditions sufficient to decrease the neurotoxicity of the beta-amyloid peptides.
• a compound of the instant invention i.e., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula Vila
• the present invention provides a method for decreasing the neurotoxicity of beta-amyloid peptides to neurons, which involves contacting the beta-amyloid peptides with a therapeutically effective amount of a compound of Formula VII and/or Formula Vila, or a pharmaceutical composition thereof.
• the neurons are human neurons.
• the compounds of the instant invention are suitable for treating diseases mediated by beta-amyloid as provided in detail above.
• the compounds as described herein can be administered at any suitable dose in the methods of increasing dendritic spine density and/or decreasing beta-amyloid peptide neurotoxicity.
• the compound is administered at a dose ranging from about 0.01 milligrams to about 1000 milligrams per kilogram of a subject's body weight (i. e., about 0.01 -1000 mg/kg).
• the dose of the compound can be, for example, about 0.01-1000 mg/kg, or about 0.1 -1000 mg/kg, or about 1 -500 mg/kg, or about 25-250 mg/kg, or about 50-100 mg/kg.
• the dose of the compound can be about 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg/kg.
• the dosages can be varied depending upon the requirements of the patient, the severity of the disorder being treated, and the particular formulation being administered.
• the dose administered to a patient should be sufficient to result in a beneficial therapeutic response in the patient.
• the size of the dose will also be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of the drug in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the typical practitioner.
• the total dosage can be divided and administered in portions over a period of time suitable to treat to the disease or condition.
• the compounds can be administered for periods of time which will vary depending upon the nature of the particular disorder (i.e., low dendritic spine density, beta-amyloid peptide neurotoxicity), its severity, and the overall condition of the subject to whom the compound is administered. Administration can be conducted, for example, hourly, every 2 hours, three hours, four hours, six hours, eight hours, or twice daily including every 12 hours, or any intervening interval thereof. Administration can be conducted once daily, or once every 36 hours or 48 hours, or once every month or several months. Following treatment, a subject can be monitored for changes in his or her condition and for alleviation of the symptoms of the disorder.
• Administration can be conducted, for example, hourly, every 2 hours, three hours, four hours, six hours, eight hours, or twice daily including every 12 hours, or any intervening interval thereof. Administration can be conducted once daily, or once every 36 hours or 48 hours, or once every month or several months. Following treatment, a subject can be monitored for changes in his or her condition and for alleviation of the symptoms of the disorder.
• the dosage of the compound can either be increased in the event the subject does not respond significantly to a particular dosage level, or the dose can be decreased if an alleviation of the symptoms of the disorder is observed, or if the disorder has been remedied, or if unacceptable side effects are seen with a particular dosage.
• a therapeutically effective amount of the compounds of the invention can be administered to the subject in a treatment regimen comprising intervals of at least 1 hour, or 6 hours, or 12 hours, or 24 hours, or 36 hours, or 48 hours between dosages. Administration can be conducted at intervals of at least 72, 96, 120, 144, 168, 192, 216, or 240 hours (i.e., 3, 4, 5, 6, 7, 8, 9, or 10 days). In certain embodiments, administration of one or more compounds of the invention is conducted in a chronic fashion over periods ranging from several months to several years.
• some embodiments of the invention provide a method of treating a disease or condition associated with low dendritic spine density or high amounts of neurotoxic beta-amyloid peptides (i.e., disorders associated with traumatic brain injury) as described herein, wherein the compound is administered to the subject for at least one year. In some embodiments, the compound is administered to the subject for at least 10 years. In some embodiments, the compound is administered to the subject for at least 60 years.
• fascin has been shown to down-regulate the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMSl).
• BRMSl breast cancer metastasis suppressor-1
• fascin up-regulates NF-kappa B activity, which is essential for metastasis.
• fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9.
• uPA urokinase-type plasminogen activator
• MMP matrix metalloproteases
• the compounds of this invention are designed to bind to fascin and, as such, to mitigate its activity and, thus, reduce tumor metastasis. Therefore, the compounds of this invention are useful in mitigating metastases of tumors.
• the compounds are administered, preferably as a pharmaceutical composition, in an effective amount as described above.
• fascin is expressed in neurons and dendritic cells. This suggests a neurological role for fascin.
• the compounds described herein bind fascin, such binding can play a critical role in understanding such neurological roles and how binding modulates those roles.
• such modulation includes mitigating the metastatic properties of fascin. In another further embodiment, such modulation includes up regulating or down regulating the neurological properties of fascin. Still further, in another embodiment, there is provided a complex of fascin with one or more molecules of Formula I, Formula IA, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula Vila as described herein. It is contemplated that such a complex will contain any appropriate binding interactions such as ionic interactions, hydrophilic/hydrophobic interactions, and where possible covalent binding.
• the present invention provides a method for reducing the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury by administering a therapeutically effective amount of a compound of the invention (i.e., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein the therapeutically effective amount of the compound, or pharmaceutically acceptable salt or solvate thereof, is an amount sufficient to reduce the symptoms of traumatic brain injury.
• the present invention provides a method for reducing the symptoms of traumatic brain injury in a patient, which involves administering a therapeutically effective amount of a compound of Formula VII and/or Formula Vila, or a pharmaceutical composition thereof.
• Traumatic brain injury may occur as a result of a head injury.
• a head injury can include any of the following: a bump to the head, a blow to the head, a jolt to the head, a sudden acceleration, a sudden deceleration, a sudden twisting of the head, a compression of the brain as a result of a nearby explosion or a penetrating head injury, and/or any type of force applied to the head which disrupts the normal function of the brain.
• a TBI can be the result of a head injury, wherein the head injury can be caused by, for example, blunt trauma to the head or a blow to the head.
• a traumatic brain injury can be a mild, moderate, or severe traumatic brain injury.
• a TBI can be a mild TBI (mTBI).
• the mildest form of TBI (mTBI) can also be called a concussion, and is characterized by a temporary loss of brain function.
• a concussed patient can temporarily lose consciousness from a few seconds up to 30 minutes.
• a patient having experienced a head injury can be diagnosed as having a mTBI by observing the patient and subsequently recognizing that the patient is experiencing symptoms of a traumatic brain injury.
• a patient having a head injury can be diagnosed as having a mTBI if the patient experiences one or more of the following conditions: (1) observed or self-reported contusion, disorientation, or impaired consciousness, dysfunction of memory at the time of the injury, loss of consciousness lasting less than 30 minutes; and, (2) symptoms such as headache, dizziness, fatigue, irritability, impaired memory and poor concentration soon after the injury.
• a patient having a head injury can be diagnosed as having a TBI by evaluating the severity of the head injury using a test or a combination of tests.
• a patient can be diagnosed as having a TBI by using the Glasgow Coma Scale (GCS).
• GCS Glasgow Coma Scale
• the GCS is an assessment that can measure and score the eye opening, verbal, and motor responses of a patient that has experienced a head injury.
• the GCS score is the sum total score of each measured response.
• a GCS score may increase or decrease over time.
• the general definition of the scores is Severe (3-8), Moderate (9-12) and Mild (13-15).
• the GCS can be implemented to evaluate the response of patients having experienced a serious traumatic brain injury (i.e., unconscious patients).
• the Glasgow Coma Scale is a commonly used method of diagnosing traumatic brain injuries in patients and is known to those skilled in the art (http://www.glasgowcomascale.org).
• a patient having a head injury can be diagnosed as having a TBI using the Rivermead Post-Concussion Questionnaire (RPQ).
• RPQ Rivermead Post-Concussion Questionnaire
• the RPQ is useful in determining the severity of several symptoms and functional deficits in a patient having been observed as having a concussion (mTBI). Patients can be asked to rate the severity of symptoms that they experience.
• the symptoms that are evaluated using the RPQ include: headaches, dizziness, nausea and/or vomiting, hyperacusis, sleep disturbance, fatigue, blurred vision, double vision, light sensitivity, restlessness, irritability, frustration, depression, memory loss, poor concentration, and taking a longer time to think. These symptoms can be evaluated within 24 hours of a patient having experienced a head injury.
• the RPQ is a commonly used method of diagnosing traumatic brain injuries in patients and is known to those skilled in the art (King, N.; Crawford, S.; Wenden, F.; Moss, N.; and Wade, D. (1995) Journal o ' Neurology 242: 587-592).
• MACE Military Acute Concussion Evaluation
• ImPACT Immediate Post-Concussion Assessment and Cognitive Test
• a patient can be diagnosed as having a traumatic brain injury by monitoring the level of particular biomarkers in the patient's blood.
• the glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase LI (UCH-Ll) are the biomarkers that can be measured at multiple time points in patients with mild to moderate TBI (i.e., a GCS 9-15).
• the blood test results measuring the levels of GFAP and UCH-Ll in the patients at multiple time points indicate whether or not a TBI has occurred.
• the levels of GFAP and UCH-Ll are both elevated very soon after a TBI, but then decline within a week to substantially lower levels. It is known to one skilled in the art how to diagnose a TBI using biomarkers (Papa, L. JAMA Neurol. (2016) 73 (5), 551-560).
• a patient can be diagnosed as having a traumatic brain injury using methods of neuroimaging, such as computerized axial tomography (CAT or CT) and magnetic resonance imaging (MRI).
• CT and MRI scans can be used to identify the severity of a brain injury.
• CT and MRI scans are often used in hospitals to identify brain injuries, though they are often not useful at detecting mTBI in which there is no obvious damage to the brain.
• patients having a mTBI with a normal CT or MRI scan can be distinguished from patients having a moderate TBI with bleeding in the brain and an abnormal CT or MRI scan.
• a CT scan may be implemented within the first 24 hours of a brain injury, and can be useful at detecting bony pathology and some types of early brain bleeds.
• An MRI scan is considered more valuable when performed 48 to 72 hours after a brain injury, and can be useful at hemorrhagic cortical contusions, petechiae, axonal injury, and subtle neuronal damage.
• the methods of neuroimaging can be most useful to patients having experienced a moderate to serious traumatic brain injury. It is known to one skilled in the art how to diagnose a TBI using neuroimaging methods (Lee, B. NeuroRX. (2005) 2 (2), 372-383; International application number PCT/US2015/024739).
• a patient can be diagnosed as having a traumatic brain injury by any one of the methods described above or known in the art, or any combination of the methods described above or known in the art.
• the patient having a head injury is diagnosed with a TBI by observation and recognition of TBI symptoms, in addition to implementing an assessment, such as the GCS or the RPQ.
• the patient having a head injury is diagnosed with a TBI by observation and recognition of TBI symptoms, in addition to monitoring biomarkers.
• the patient having a head injury is diagnosed with a TBI using multiple assessments, such as the GCS, RPQ, and MACE.
• the patient having a head injury is diagnosed with a TBI using neuroimaging methods, in addition to monitoring biomarkers and performing an assessment, such as the GCS or the RPQ.
• the patient having a head injury is diagnosed with a TBI using neuroimaging methods, in addition to monitoring biomarkers.
• the patient having a head injury is diagnosed with a TBI using neuroimaging methods, in addition to performing an assessment, such as the GCS or the RPQ.
• the patient having a head injury is diagnosed with a TBI using neuroimaging methods, such as MRI and CT scans.
• the patient having a head injury is diagnosed with a TBI by monitoring the levels of biomarkers.
• the patient having a head injury is diagnosed with a TBI by observation and recognition of TBI symptoms. In other embodiments, the patient having a head injury is diagnosed with a TBI using one assessment, such as the GCS or RPQ. In some embodiments, the patient having a head injury is diagnosed with a TBI using the RPQ assessment.
• a patient having a head injury is diagnosed with a TBI using any of the methods and assessments described herein immediately after receiving the head injury, i.e. within 0 hours of receiving a head injury.
• the patient having a head injury is diagnosed with a TBI within about 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 4 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours or 48 hours of receiving a head injury.
• a patient having a head injury is diagnosed with a TBI within about 0 to about 48 hours of receiving a head injury, or about 5 minutes to about 42 hours, or about 10 minutes to about 36 hours, or about 15 minutes to about 30 hours, or about 20 minutes to about 24 hours, or about 30 minutes to about 18 hours, or about 45 minutes to about 12 hours, or about 1 to about 4 hours of receiving a head injury.
• a patient having a head injury is diagnosed with a TBI within about 0 hours to about 1 hour of receiving a head injury. In another embodiment, a patient having a head injury is diagnosed with a TBI within about 30 minutes of receiving a head injury. [0192] In some cases, patients diagnosed with a concussion/mTBI and more serious TBIs can experience neurological effects caused by altered levels of neurochemicals, and subsequent neuron damage. The neurological effects can linger for days, weeks, months or years. These neurological effects cause deficits in the following functional domains:
• Deficits of the physical domain can induce any of the following symptoms: nausea, vomiting, dizziness, headaches, seizures, changes in consciousness, fatigue, weakened muscles, impaired balance, and/or impaired coordination.
• Deficits of the visual domain can induce any of the following symptoms: light sensitivity, double vision, decreased visual acuity, visual neglect, and/or changes in the accommodation-convergence reflex.
• Deficits of the auditory domain can induce any of the following symptoms: hyperacusis, tinnitus, hearing loss, and/or central auditory dysfunction.
• Deficits of the neurobehavioral domain can induce any of the following symptoms: agitation, anxiety, depression, mood swings, restlessness,
• Deficits of the cognitive-communication domain can induce any of the following symptoms: attention deficits, executive function deficits, information processing impairments, memory deficits, learning deficits, impaired metacognition, impaired spatial cognition, aphasia, and/or motor speech deficits.
• Deficits of the sleep domain can induce any of the following symptoms: insomnia, hypersomnia, and/or sleep disturbance.
• a patient diagnosed with a TBI can have a deficit in one or more functional domains.
• a patient diagnosed with a TBI having a deficit in one or more functional domains can receive a therapeutically effective amount of a compound of the invention (i.e., a compound of Formula I, Formula IA, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula Vila).
• a patient diagnosed with a TBI having a deficit in one or more functional domains can receive a therapeutically effective amount of a compound of Formula VII and/or Formula Vila, or a pharmaceutical composition thereof.
• a patient diagnosed with a TBI having a deficit in one or more functional domains can receive a therapeutically effective amount of a compound, or pharmaceutically acceptable salt or solvate thereof, according to formula:
• Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the traumatic brain injury and state of the patient.
• suitable dosage ranges for the active agent include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg.
• suitable dosages for the active agent include about 1 mg, 5, 10, 20, 30, 40,
• the dosage of a pharmaceutical composition for oral administration of a compound described herein can be about 0.1 mg/kg of body weight per patient, or 0.5, 1, 5, 10, 25, 50, 100, 250, 500, 750, or 1000 mg/kg of body weight per patient. In other embodiments, the dosage of a pharmaceutical composition for oral administration of a compound described herein can be from about 0.1 to 1000 mg/kg of body weight per patient, or from about 0.5 to 750, or from about 1 to 500, or from about 5 to 250, or from about 10 to 100, or from about 25 to 50 mg/kg of body weight per patient.
• the dosage can be between about 0.5 to about 25 mg/kg of body weight per patient, or between about 5 to 15 mg/kg of body weight per patient, or between about 8 to about 12 mg/kg of body weight per patient, or about 10 mg/kg of body weight per patient.
• Lower dosages can be used, particularly when the drug is administered to an anatomically secluded site, such as the cerebral spinal fluid (CSF) space, in contrast to administration orally, into the blood stream, into a body cavity or into a lumen of an organ.
• CSF cerebral spinal fluid
• the active agent can be present in the compositions of the present invention in any suitable weight ratio, such as from about 1 : 100 to about 100: 1 (w/w), or about 1 :50 to about 50: 1, or about 1 :25 to about 25: 1, or about 1 : 10 to about 10: 1, or about 1 :5 to about 5: 1 (w/w).
• the active agent can be present in any suitable weight ratio, such as about 1 : 100 (w/w), 1 :50, 1 :25, 1 : 10, 1 :5, 1 :4, 1 :3, 1 :2, 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 25: 1, 50: 1 or 100: 1 (w/w).
• a patient having been diagnosed with a TBI can be administered a therapeutically effective amount of a compound (including embodiments, examples, and/or pharmaceutical compositions thereof) in a dosage described above immediately after receiving the TBI, i.e. within 0 hours of receiving the TBI.
• the patient having a TBI can be administered a therapeutically effective amount of a compound within about 10 minutes of receiving the TBI, or within about 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, or 72 hours of receiving the TBI.
• a patient having a TBI can be administered a therapeutically effective amount of a compound within about 0 to about 72 hours of receiving the TBI, or within about 10 minutes to about 48 hours, or within about 20 minutes to about 36 hours, or within about 30 minutes to about 30 hours, or within about 45 minutes to about 24 hours, or within about 1 to about 18 hours, or within about 2 to about 12 hours, or within about 4 to about 7 hours of receiving the TBI.
• a patient having a TBI can be administered a therapeutically effective amount of a compound within about 0 to 24 hours of receiving the TBI.
• a patient having a TBI can be administered a therapeutically effective amount of a compound within about 18 hours of receiving the TBI. In other embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a compound within no more than 18 hours of receiving the TBI. In certain embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a compound within 4 hours of receiving the TBI. In some other certain embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a compound within 1 hour of receiving the TBI.
• a patient having a TBI can be administered a therapeutically effect amount in a dosage described above of a compound (including embodiments, examples, and/or pharmaceutical compositions thereof) at least once per 30 minutes, or 1 hour, 2 hours, 3 hours, 4 hours, 6, hours, 8 hours, 12 hours, 18 hours, or 24 hours.
• a patient having a TBI is administered a dose of a compound (including embodiments, examples, and/or pharmaceutical compositions thereof) at least once per 30 minutes, or 1 hour, 2 hours, 3 hours, 4 hours, 6, hours, 8 hours, 12 hours, 18 hours, or 24 hours.
• a patient having a TBI is administered a dose of a compound (including embodiments, examples, and/or pharmaceutical compositions thereof) at least once per 30 minutes, or 1 hour, 2 hours, 3 hours, 4 hours, 6, hours, 8 hours, 12 hours, 18 hours, or 24 hours.
• a patient having a TBI is administered a dose of a compound (including embodiments, examples, and/or pharmaceutical compositions thereof) at least
• composition of a compound at least once per 30 minutes to 24 hours, or at least once per 1 hour to 18 hours, or at least once per 2 to 12 hours, or at least once per 3 to 8 hours, or at least once per 4 to 6 hours.
• a patient having a TBI can receive a treatment regimen as described above (i.e. dosage and dosage frequency of a therapeutically effective amount of a compound of Formula (VII) or Formula (Vila)) for any suitable length of time.
• a patient having a TBI can receive a treatment regimen for about 1 day, or 2, 3, 5, 7, 10, 14, 20, 25, 30, 35, 45, 60, or about 90 days.
• a patient having a TBI can receive a treatment regimen for about 1 day to about 90 days, or about 2 to about 60, or about 3 to about 45, or about 5 to about 35, or about 7 to about 30, or about 10 to about 25, or about 14 to about 20 days.
• a patient having a TBI can receive a treatment regimen for about 35 days.
• a patient diagnosed with a traumatic brain injury who has received treatment for reducing the symptoms of the traumatic brain injury as described above i.e., a patient being administered a therapeutically effective amount of a compound
• a patient being administered a therapeutically effective amount of compound can be evaluated for an improvement in the performance of one or more functional domains (i.e., physical, visual, auditory, neurobehavioral, cognitive-communication, and sleep).
• a patient being treated for a TBI can be evaluated for an improvement in one or more of the functional domains using any one of the methods used to diagnose the patient with a TBI (as described herein or known in the art), or any combination of such methods.
• a TBI patient receiving a treatment regimen described above can be evaluated for an improvement in one or more of the functional domains by monitoring the level of GFAP and UCH-L1 biomarkers in the patient's blood and/or using any of the following assessments: GCS, RPQ, MACE, ImPACT, SCAT, ANAM, and/or Cogstate.
• a TBI patient receiving a treatment regimen can be evaluated for an improvement in one or more of the functional domains using GCS, RPQ, and/or MACE. In other embodiments of the invention, a TBI patient receiving a treatment regimen can be evaluated for an improvement in one or more of the functional domains using GCS and RPQ. In certain embodiments of the invention, TBI patient receiving a treatment regimen can be evaluated for an improvement in one or more of the functional domains using RPQ.
• a TBI patient receiving treatment can be evaluated for an improvement in the performance of one or more functional domains for any suitable number of times during the span of a TBI treatment regimen. In some embodiments of the invention, a TBI patient receiving treatment can be evaluated for an improvement in the performance of one or more functional domains at least 1 time per treatment regimen, or about 2, 3, 6, 12, 15, 18, 20, 25, 30, 40, 50, 60, 80, 100, or 150 times per treatment regimen.
• a TBI patient receiving treatment can be evaluated for an improvement in the performance of one or more functional domains about 1 to about 150 times per treatment regimen, or about 2 to about 100, or about 3 to about 80, or about 6 to about 60, or about 12 to about 50, or about 15 to about 40, or about 18 to about 30, or about 20 to about 25 times per treatment regimen.
• a TBI patient receiving treatment can be evaluated for an improvement in the performance of one or more functional domains about 3 to about 80 times per treatment regimen.
• a TBI patient receiving a treatment regimen for about 35 days can be evaluated for an improvement in the performance of one or more functional domains anywhere between 3 and 80 times during the 35 day span of treatment regimen.
• the reduction of the symptoms of traumatic brain injury in a TBI patient can be observed as an improvement in the performance of one or more functional domains in the TBI patient.
• an improvement in the performance of one or more functional domains in a TBI patient can be observed as a reduction of the symptoms of traumatic brain injury in the TBI patient.
• the measured performance of one or more functional domains in a patient will improve by a percentage (%) compared to the performance of the one or more functional domains measured prior to treatment but after injury.
• the performance of one or more functional domains can improve by at least 1% compared to the performance of the one or more functional domains measured prior to treatment but after injury, or by at least 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70 or 80% compared to the performance of the one or more functional domains measured prior to treatment but after injury.
• the measured performance of one or more functional domains in a patient can improve by at least 1% to 80% compared to the performance of the one or more functional domains measured prior to treatment but after injury, or by at least 1 % to 80%, or by at least 5% to 70%, or by at least 10% to 60%, or by at least 15% to 50%, or by at least 20% to 40%, or by at least 25% to 35% compared to the performance of the one or more functional domains measured prior to treatment but after injury.
• the performance of one or more functional domains can improve by at least 20% to 30% compared to the performance of the one or more functional domains measured prior to treatment but after injury.
• the performance of one or more functional domains can improve within any suitable amount of time of treatment.
• the performance of one or more functional domains can improve within about 24 hours of treatment, or within about 48 hours, 72 hours, 5 days, 7 days, 14 days, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, or 20 weeks of treatment. In some embodiments of the invention, the performance of one or more functional domains can improve within about 24 hours to about 20 weeks of treatment, or within about 48 hours to about 16 weeks, or within about 72 hours to about 12 weeks, or within about 5 days to about 8 weeks, or within about 7 days to about 6 weeks, or within about 14 days to about 4 weeks of treatment. In certain embodiments, the performance of one or more functional domains can improve within about 7 days to about 4 weeks of treatment. In other particular embodiments, the performance of one or more functional domains can improve within about 7 days of treatment. VII. Examples
• Step A. Preparation of 4-(benzo[d]thiazol-2-yl)phenol (1). All reagents were obtained from Sigma Aldrich and used as such. To 40 mL of a 1: 1 ethanol/water solvent mixture was added scandium triflate (Sc(OTf)3, 1 g, 2 mmol), 2-aminobenzenethiol (1.2, 3.6 g, 28.8 mmol), and 4-hydroxybenzaldehyde (1.1, 3.6 g, 29.5 mmol). The reaction mixture was stirred at 50 °C overnight in an open flask. After completion of the oxidation reaction, the reaction was cooled to room temperature (r.t.) and filtered. The isolated solids were washed with ether and dried, producing 4-(benzo[d]thiazol-2-yl)phenol (1) in a 70-80% yield.
• Sc(OTf)3 scandium triflate
• 2-aminobenzenethiol 1.2, 3.6 g, 28.8
• Step B. Preparation of tetraethylene glycol /7-toluenesulfonate (2). All reagents were obtained from Sigma Aldrich and used as such. To a solution of tetraethylene glycol (2.2, 3.88 g, 20 mmol) in 100 mL of dichloromethane was added tosyl chloride (2.1, 3.8 g, 20 mmol). The reaction mixture was then cooled to -78 °C before slowly adding triethylamine (2.01 g, 20 mM) dropwise and stirred overnight. The reaction mixture was allowed to slowly warm to r.t. before washing with 1 L of water and drying to afford the crude product.
• Example 2 In vitro spinogenesis using benzothiazole compounds.
• Compounds of the current invention bind to the actin bundling protein, fascin, and prevent the formation of long, stiff actin cytoskeleton, thereby promoting dendritic spine formation, (see, Sedeh, R. S. et al. J. Mol. Biol. 400, 589-604 (2010); Chen, L. et al. Nature 464, 1062-1066 (2010); Jansen, S. et al. J. Biol. Chem. 286, 30087-30096 (2011); Yang, S. et al. J. Biol. Chem. 288, 274-284 (2013); Zheng, S. et al. J. Med. Chem.
• Benzothiazole-IIIA and Benzothiazole-IIIB all cause an increase in the number of synaptic puncta compared to the vehicle control.
• Hydrogen atoms were added to the structures, and considerations were made regarding: correct orientation of Asn and Gin side-chains, ligand and protein charges, histidines orientation and protonation state, and any crystallographic quality flags, such as high b-factors or low occupancy.
• MolSoft's ICMPocketFinder algorithm was used to identify potential ligand binding pockets and cavities in all the available Fascin crystal structures (see, An, J., et al. Genome Inform. Int. Conf. Genome Inform. 15, 31-41 (2004); Kufareva, I., et al. Nucleic Acids Res. 40, D535-540 (2012)).
• pockets in the active chain A of crystal structure 3LLP were searched, as this structure had the highest resolution (1.8A).
• Four "drug-like" pockets were identified as having properties suitable for binding small molecules (FIG. 4).
• Benzothiazole-IIIA were docked to each of the four pockets shown in FIG. 4 using MolSoft's ICM-Docking software, Version 3.8-6a (Abagyan, R. & Totrov, M. J. Mol. Biol. 235, 983- 1002 (1994)).
• the docking scores to each of the pockets are shown in Table 6. The lower the docking score the better the "compound-fascin binding pocket" interaction.
• Example 4 Treating TBI symptoms in an adult male with a benzothiazole compound.
• a 17-year old male patient without prior history of traumatic brain injury is experiencing disorientation, dizziness and a headache after having been unconscious for about 30 seconds as a result of being tackled during a football game.
• the patient's symptoms are observed and it is recognized that the head injury can be diagnosed as a TBI.
• a medical specialist at the scene confirms the patient's diagnosis of a moderate to mild traumatic brain injury using the Rivermead Post- Concussion Questionnaire, with a score of 32.
• the results of the RPQ assessment also showed that the patient was experiencing sensitivity to light, irritability, and aphasia.
• the patient is administered treatment for his traumatic brain injury.
• Benzothiazole-IIIB a benzothiazole compound
• daily doses of Benzothiazole-IIIB in the range of 1155 mg per day, over a period of about 14 to 35 days, will be used as an effective treatment for TBI.
• the patient's progress will be monitored by administering the RPQ assessment and will provide the barometer of the patient's overall improvement from treatment using the methods of the invention.
• the RPQ assessment will be given both before administration of Benzothiazole-IIIB (i.e., to diagnose the patient) and after administration of Benzothiazole-IIIB.
• the RPQ assessment will be carried out on days 1, 7, 14, 21, 28 and 35.
• the patient will be given 1155 milligrams of Benzothiazole-IIIB once per day orally, over 35 days.
• the patient's Rivermead Post- Concussion Questionnaire scores are expected to decline from about 32 to about 24. This is indicative of a 25% improvement in the performance of one or more functional domains, specifically the physical, visual, cognitive-communication, and neurobehavioral domains.
• the results of the RPQ are evaluated after the 35 day period, the patient will show an amelioration of a traumatic brain injury. Indeed, the patient is expected to improve in the performance of the effected domains by about 30% to 70% after the 35-day treatment.
• This example illustrates how doses of benzothiazole compounds, in the range of about 1155 mg per day, given once daily over a relatively short period of time— about 35 days— are expected to reduce the symptoms of traumatic brain injury in a human patient.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (1)

Family

ID=65234154

Family Applications (1)

Country Status (8)

Cited By (3)

Citations (2)

Family Cites Families (7)

• 2018
  • 2018-08-01 EP EP18840208.5A patent/EP3661505A4/en active Pending
  • 2018-08-01 CA CA3071525A patent/CA3071525A1/en active Pending
  • 2018-08-01 CN CN201880062871.2A patent/CN111163773A/zh active Pending
  • 2018-08-01 MA MA049766A patent/MA49766A/fr unknown
  • 2018-08-01 AU AU2018312558A patent/AU2018312558B2/en active Active
  • 2018-08-01 WO PCT/US2018/044852 patent/WO2019028164A1/en unknown
  • 2018-08-01 US US16/635,872 patent/US11117878B2/en active Active
  • 2018-08-01 JP JP2020506266A patent/JP7168650B2/ja active Active
• 2021
  • 2021-08-02 US US17/392,036 patent/US20220017477A1/en active Pending
• 2022
  • 2022-10-27 JP JP2022172487A patent/JP7465323B2/ja active Active
• 2024
  • 2024-03-29 JP JP2024057101A patent/JP2024074871A/ja active Pending

Patent Citations (2)

Also Published As

Similar Documents

Legal Events